Jb. Huang et al., Prevention of arterial thrombosis by intravenously administered platelet P2T receptor antagonist AR-C69931MX in a canine model, J PHARM EXP, 295(2), 2000, pp. 492-499
Citations number
30
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
P2Y1, P2X1, and P2T receptors mediate ADP-induced platelet aggregation. The
antithrombotic effects of AR-C69931MX (N6-[2- methylthio)ethyl]-2-[3,3,3-t
rifluoropropylthio]-5'-adenylic acid, monoanhydride with dichloromethyleneb
iphosphonic acid), a selective P2T platelet receptor antagonist, was assess
ed in a canine model of arterial thrombosis. Placebo or AR-C69931MX (4.0 mu
g/kg/min for 6 h) pretreatment was administered as an intravenous infusion
beginning 15 min before inducing vessel wall injury. A 300-muA anodal curre
nt was applied to the intima of the carotid artery for 180 min or discontin
ued 30 min after cessation of blood flow due to thrombus formation. Each of
five control animals developed occlusive thrombi within 3 h after inductio
n of vessel wall injury. In contrast, carotid artery blood flow in five of
six AR-C69931MX-treated animals was maintained for the duration of the prot
ocol. Ex vivo platelet aggregation in response to adenosine diphosphate was
inhibited at the first measurement time point of 75 min after the start of
drug infusion and remained inhibited during drug administration. Bleeding
time values were increased in the drug-treated group. Values for both the e
x vivo platelet aggregation and the bleeding times returned to control valu
es shortly after discontinuation of AR-C69931MX. The results indicate that
AR-C69931MX antagonizes the ex vivo and in vivo aggregatory actions of ADP,
and displays a rapid onset and offset of action with the ability to preven
t occlusive arterial thrombus formation. AR-C69931MX may be suitable for th
e management of patients who require short-term modulation of platelet func
tion.